TW201120035A - Proline derivatives - Google Patents

Abstract

Compounds of formula (I): wherein A, B, C, D, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, m, n, p, q, r, t, u, and v are defined herein. Also disclosed is a method for treating hepatitis C virus infection with these compounds.

Description

201120035 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to a proline derivative. The present application claims priority to U.S. Provisional Application Serial No. 61/266,584, filed on Dec. [Prior Art] It is estimated that 170 million people worldwide are infected with hepatitis C virus (HCV). This disease is mainly transmitted through contaminated blood products, although its rate of transmission has slowed down due to improved blood screening in many countries. However, it is still the primary cause of death from liver disease in the world. In the United States alone, it can cause about 10,000 deaths per year. However, in the absence of effective treatment, the mortality rate will be tripled after 20 years. At present, the use of interferon- (X treatment, especially for genotypic infections prevalent in the United States, Sakamoto and Europe, has a low success rate, and its price is high, and patient acceptance is poor. Therefore, it needs to develop better. Therapeutic agents for the treatment of HCV infections. SUMMARY OF THE INVENTION The present invention unexpectedly finds certain polycyclic compounds that are effective in treating hepatitis C virus infection. In one aspect, the invention relates to a compound of formula (I).

Λ:η

B is < or N, o' s ; C and D are each arylene or heteroarylene; h, r2, r3, R4, 5 and r6 are each alkyl, alkenyl, alkynyl, aryl , heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halogen, heterocycloalkenyl, cyano or nitro; feet 7 and 118 are individually H, alkyl, alkenyl, block, aryl , heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; RAR1() is independently hydrazine or alkyl; Rn and Rl2 are each H, alkyl, alkenyl, alkynyl, aryl a group, a heteroaryl group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group or a heterocycloalkenyl group; χ, & Χ2 is individually C(0) or c(s); Υι& γ2 is absent or individually SO , S02, C(O), C(0)0, C(0)NRa, C(S)NRa or S〇zNRa, wherein Ra is H, alkyl, cycloalkyl, heterocycloalkyl, aryl or Heteroaryl; m and η are each 〇, 1, 2, 3 or 4; p and q are each 〇 or 1; r and t are each 2 or 3; and u and v are 〇, Bu 2, 3 , 4, 5, 6, 7, or 8. For example, the compound of the present invention is of the formula (11): 5 201120035

Specifically, the compounds are of formula (III):

A

R12 The above compounds may include more than one of the following features. ;

Α and Β are each? C and D are each phenylene; & and \ are each C(O); Υ, & Υ2 are individually S〇2, C(0) or C(〇)〇; Each of the cores is a phenyl group; Rm and R12 are each a Cw alkyl group or a C3-5 cycloalkyl group; each is 2; A and B are different; p, m, η, q, u, and v are each 0; p, m, η and q are each 〇, u and v are each 1 and 115 and 6 are each f » The term "alkyl" refers to a straight or branched monovalent hydrocarbon group, which contains 1-20 Carbon atoms (e.g., c丨-C1 〇), examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl groups. The term "alkenyl" refers to a straight or branched monovalent hydrocarbon group containing 2 to 2 carbon atoms (eg, C 2 -Cl 0 ) and more than one double bond. Examples include, but are not limited to, vinyl , propylene (pr〇peny丨) and allyl (ally) "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-20 carbon atoms of 201120035 (eg C2-C1() With more than one triple bond, the alkynyl group includes, but is not limited to, an ethylene group, a 1-propyl block group, a b- and a 2-butyl block group, and an i-methyl group. A soap-saturated hydrocarbon ring structure having from 3 to 30 carbon atoms (e.g., C^-Cu). The examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and ring. Heptyl and cyclooctyl. The term "cycloalkenyl" refers to a monovalent non-aromatic hydrocarbon ring structure having from 3 to 3 carbon atoms (eg CyC! 2) and more than one double bond, cycloalkyl Examples include: cyclopentenyl, cyclohexenyl and cycloheptenyl. "Heterocyclic alkyl" means a monovalent non-aromatic 5- 8 membered monocyclic structure, 8-12 membered bicyclic structure or 11-14 member The ring structure 'has more than one hetero atom (e.g., hydrazine, N, S or Se), and examples of heterocycloalkyl include, but are not limited to, piperazinyl, pyrr〇iidinyl, dioxane. Dioxanyl, morph〇linyi, and tetrahydrofuranyG. The term "heterocycloalkenyl" refers to a monovalent non-aromatic 5-8 membered monocyclic structure, 8-12 membered bicyclic structure, or u_14 member. a tricyclic structure having more than one hetero atom (eg, 〇, N, s, or Se) and more than one double bond. The term "aryl" refers to a unit price (: 6 monocyclic, C1 〇 bicyclic or C14 tricyclic aromatic ring system, aryl groups include, but are not limited to, phenylnaphthyl and anthracenyl. The term "arylene" refers to a divalent c6 monocyclic (eg, phenylene), C 丨 0 double a cyclic (e.g., naphthylene) or Ci4 tricyclic aromatic ring system. The term "heteroaryl" refers to a monovalent aromatic 5-8 membered single ring, 8.12 membered bicyclic ring or 11]4 membered tricyclic structure having More than one hetero atom (eg, 0, N, S or Se), examples of heteroaryl include: pyridyl, furyl, imidazolyl (lm idaZ〇lyl), benzimidazoly, pyrimidyl 201120035 (pyrimidinyl), thienyl, quin〇iinyi, indolyl and sold. Thiazolyl). The term "heteroarylene" refers to a bivalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic structure having more than one heteroatom (eg, 〇, N). , S or Se)» Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, arylene, heteroaryl and heteropoly as described herein.彡基_ , includes two base circles, substituted and unsubstituted. Possible substituents on cycloalkyl, heterocyclic, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups include, but are not limited to, Ci-Ci oxime (eg, trifluoromethyl), C2 a -C10 dilute group, a c2_c16 block group (for example, an aryl group), a C3-C2 anthracene group, a C3-C2 anthracene group, and a q_c2 group. Heterocyclic alkyl, C^-C2!) heterocyclic, Ci-Cio alkoxy, aryl (eg, aryl or halogen substituted aryl), aryloxy, heteroaryl, heteroaryloxy Base, amine group, Cl-Cl oxime, arylamine, thiol, halogen, oxo (〇=), thio (S = ), thiol, dream base, Cl-ClQ^ Thiol group, aryl thiol group, CrCio alkylsulfonyl, aromatic aryl, acylamino, aminoacyl, amine thiol sulfhydryl Aminothioacyl), amidino, mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine ), ureido, cyano, nitro, acyl, thioacyl, acyloxy, carbamido, carbamyl, oxic acid Carboxyl and carboxylic acid. On the other hand, possible substituents on a fluorenyl, fluorenyl or alkynyl group include all of the above substituents, 201120035 except for the q-Cw alkyl group. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be fused to each other. The above polycyclic compounds include the compounds themselves, as well as the salts, solvates and precursors thereof which can be carried out. For example, a salt may be formed by a polycyclic compound having a positively charged group (eg, a sulfhydryl group) and an anion, and a suitable anion includes a gas ion, a bromide ion, an iodide ion, a sulfate group, an arsenic sulfate, and a amide. Acid, nitrate, phosphate, citrate, sulfonate, trifluoroacetate, proline, aldanoate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluene Sulfonic acid, salicylate, lactate, naphthalenesulfonate and acetate beta. Similarly, salts can also be formed from negatively charged groups (such as carboxylates) and cations on polycyclic compounds, while suitable cations contain nanoions. , potassium, magnesium, calcium and ammonium (such as tetramethylammonium). Polycyclic compounds also include such salts containing a quaternary nitrogen atom, and the prodrug forms include, for example, esters and other pharmaceutically acceptable derivatives, which are capable of providing more activity depending on the mode of administration to the subject. Ring compound. In another aspect, the invention is directed to a method of treating an Hcv infection by administering one or more of the foregoing effective doses of a polycyclic compound to a subject infected with HCV. Further, a pharmaceutical composition comprising the above polycyclic compound and used for the treatment of HCV infection, and the use of the therapeutic use and the use of the compound to produce a therapeutic agent for hcv infection are also within the scope of the present invention. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. [Embodiment] Table 1 below shows an exemplary compound of the present invention. Table 1

201120035 7c-B Q 6 〇 987 25a 893 26a 829 29a 910 30a 846 33a 910 34a 846 37a 908 38a 844 201120035

12 201120035 56a 893 57a 893 58a 921 59a 921 60a 865 61a 865 62a 921 63a 921 64a 893 65a 893 66a 889 13 201120035

14 201120035

15 201120035

201120035

201120035 125a 861 126a 861 127a 861 128a 657 129a 657 Some additional examples of compounds are also shown below:

18 201120035

The compounds of the present invention can be prepared using known chemical transformation methods, including protecting group methodology, such as R. Larock, Cowpre/zenj/ve Organic Transformationst VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, /«

Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic 19 201120035 iSywi/ieji·?, John Wiley and Sons (1994); and L. Paquette, ed Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions thereof. The following Schemes 1 to 13 represent the conversion process for synthesizing the compound of the present invention. Scheme 1 shows the preparation of symmetrical dithiazolylbiphenyl analogs 7a-c. 2-Amino-1·(4-bromophenyl)ethanone hydrochloride is combined with ΛΓ-Boc-L-proline (iV-Boc-L-proline) to produce 1,4-diyl Compound la-c, followed by treatment of the 1,4-diyl intermediate la-c with Lawesson's reagent yields the aryl bromide 2a-c. In order to construct a symmetric biphenyl skeleton, aryl bromide 2a-c reacts with bis (pinacolato diboron) to form the corresponding aryl boronate 3a-c, which is coupled to the Suzuki-Miyaura coupling ( A symmetrical dithiazolylbiphenyl group (compounds 4a-c) can be obtained by coupling with another equivalent arylthiazole bromide 2a-c under Suzuki-Miyaura coupling conditions. Removal of the AM-protecting group of the compound 4a-c in an acid, the derivative 5a-c can be obtained, which is coupled with the phenylglycine of the hydroxy group to obtain the symmetric biphenyl peptide 6a-c The acid treatment 6a-c removes the Boc-protecting group, and the crude product is then reacted with a different alkyl or aryl oxime gas to obtain the final deuterated product 7a-c 0 20 201120035

ο Process 1

Ia>c

OkPEA CHsCI» r.t, lOmln

Rt•reverse aW:〇c’CH*a2

«: Rt aH; ^2° H brR^F; R, « H^c: R1-H; R2» F Another synthetic route is shown in Scheme 2 below, which can be used to obtain symmetric dithiazilbiphenyl Analogs 7a-c. In this synthetic route, the intermediate 4,4'-bis(2-((5)-D-pyridin-2-yl)thiazol-5-yl)biphenyl (4,4,_bis(2-() (6·)-pyrrolidin-2-yl)thiazol-5-yl)biphenyls, compounds 5a-c) can be prepared by a similar method as shown in Scheme 1 'Subsequently complexing 5a-c with compound 8 gives analog 7a-c . Process 2 21 201120035

fS + (10) person ~-H〇BtH^°-EDc Λ) ° CHaCy sigh reacted A

〇Λ〇Λ·'ΝΗ2 〇 H〇\'VRi, certain compounds. For example, the various polyheteroaryl groups of the compounds of the invention may be derived from heteroaryl bromides (such as 12a~c, 16a~c, or 21a~c as shown in Scheme 3-6) and aryl boronate derivatives ( For example, it is also synthesized by coupling 13a to c, 20a to c, or 22a to c) shown in the following Scheme 3-6. As shown in the following Scheme 3, commercially available iV-Boc-L-proline acids 9a to c can be directly converted into good yields of primary guanamines 10a to c using ammonium carbonate using a simple method. Treatment with Lawson's reagent under temperature increase (Phantom-iV-Boc decylamine decylamine 10a~c, available (5>iV-Boc thiocarbamyl pyrrolidine (Q-iV-Boc carbamothioylpyrrolidine) 11a ~c, 118~<; and 4-bromophenacyl bromide are condensed at room temperature to form high yield 1,3-thiazole 12a~c. Boron as a substrate 'Miyaura boration' was used to prepare octagonal aryl boronate derivatives 13a to c, in which PdCl 2 (<ippf) and potassium acetate were used as catalysts. Flow 3 22 201120035 _ ^'R2 3 (b〇c) 2o, (nh4)2c〇3, pyridine

Lawson's reagent THF. 70°C, 8hr

Lla~c H〇 Boc 1,4-dioxane,|".〖..19咁 9a: R^H; R2=H i〇a^c

Dipenta-as diboron PdCiydppf). KOAc DMSO, 80 ° C. 2.5h The 4-bromobenzonitrile 14 and the amine hydrochloride can be refluxed in an alkaline matrix as shown in Scheme 4 below. (hydroxylamine hydrochloride) to prepare amidoximes 15 (including synergistic and / or antagonistic isomers), without further purification, the preparation of bromophenyl 1,2,4-oxadiazole derivatives 16a using amidoxime 15 ~c. More specifically, 4-bromobenzamidoxime 15 and the commercially available iV-protected L-amino acid 9a~c are subjected to a condensation reaction in an alkaline environment to obtain a compound having a good yield. 16a~c. Process 4

14 nh2oh.hci, dipea EtOH, 90°C, 5h r, \ N-^OH X=/ nh2 9a*c , TBTU, H0Bt.H20, DIPEA DMFf110°C, 2.5h 15

Boc

16a: R^; R2=H 16b: Ri=F; R2=H 16c: Ri=H; R2=F 23 201120035 As shown in the following Scheme 5, the amine aryl ethyl ketone salt 17 and #-Boc-l-脯The amine acids 9a-c are coupled to provide compounds 18a-c which can be used to prepare both phenylimidazole (as shown in Scheme 5) and phenylthiazole (as shown in Scheme 6). Under the heating condition with ammonium acetate, the compounds 18a~c can then be subjected to a cyclization reaction to form phenylimidazole bromide derivatives 19a~c, which can be converted to imidazolyl aryl boronate by the halope hydrolysis reaction of the palace. Object 20a~c. Process 5

NH4〇Ac, AcOH dimethyl stupid, 160eC. 3h

As shown in the following Scheme 6, the phenylthiazole bromide 21a-c can be produced in a short time by using the Lawson's reagent to reflux the compounds 18a to cc. The aryl boronic acid ester derivatives 22a to c can be produced by subjecting phenylthiazole bromide 21a~c to a halope hydrolysis reaction. Process 6

18b: R,=F; R2=H 18c: R^H; R2=F

24 201120035 The polycyclic compound of the present invention can also be synthesized from a bipartite compound as shown in the following Scheme 7. Process 7

1. Dimethyl sulphate CH3CN, reflux, h Br 2.5% Ηα in acetonitrile, turbulent, 4h

H3N

Scheme 8 below illustrates another modified process for preparing the polycyclic compounds of the present invention. In this synthetic route, the intermediate 4,4'-bis(2-((5> pyrrolidin-2-yl)thiazol-5-yl)biphenyl (compound 5a in Scheme 1) must be coupled to the compound 93. Or 94 to obtain the analogs 95a-105a and 106a-114a.

□ 25 201120035 The following Scheme 9 shows a method for synthesizing dithiazolylbiphenyl 119a which is a stereoisomer of dithiazolylbiphenyl 5a. Process 9

Scheme 10 shown below illustrates the synthesis of dithiazolyl biphenyl peptides 6a, 120a, 121a and 122a from compounds 5a and 119a by peptide coupling conditions (e.g., HOBt. H20 and EDC) to remove the dithiazolyl biphenyls. After the protecting group of the peptide, it is then reacted with a different alkyl or aryl acetic acid gas to produce the desired compound 7a and 123a-127a. 26 201120035 Process ίο

27 201120035 The following Schemes 11 to 13 show typical synthetic routes of the polycyclic compounds of the present invention. Coupling conditions of aryl bromide (for example, 12a~c, 16a~c, or 2U~c) and aryl boronate (such as 13a~c, 20a~c, or 22a~c) in eucalyptus The reaction is carried out to construct a ΛΓ·protective asymmetric biphenyl compound*23a~c (as shown in Schemes 7 to 9). The pyrrolidine group is deprotected in trifluoroacetic acid at room temperature to yield the deprotected derivative 24a~c, which is then coupled to W-Boc-d-phenylglycine. An asymmetric biphenyl compound 25a~c is obtained. In a one-step process, 25a~c can be treated with trifluoroacetic acid and then reacted with a different alkyl or aryl acetic acid gas to provide the final deuterated product 26a-c. Similarly, other substituted compounds can be prepared (e.g., 3〇a~c, 34a~c, 38a~c, 42a~c, and 46a~c as shown in the following Schemes 11 to 13). 28 201120035 Process 11

Be

16a: χ=Ν, Υ=0, Ζ=Ν 16r: Χ=Ν, V=0, 2=Ν 16a: Χ=Ν.Υ=0. Ζ=Ν 12a: X=CH. Y=S, 2 =Ν 21a: X=CH, Y=N, Z=S 21a: X=CH, Y=N, Z=S

20a: X=CH 13a: X*=CH 22n: X=CH 20fl: >C=CH 20a: X*=CH 13*»:X*=CH

Y'=NH, Z=N r=s, Z=N Y.=N, Z.=S Y.=NH,2T=N Υ·=ΝΗ.Ζ·=Ν Y.=S,Z,=N

23a: X=N, Y=〇, Z=N; X^CH, Y'^NH, Z^N 27a: X=N, Y=Of Z=N; X*=CH, r=S, Z' =N 31a: X=N, Y=0, Z=N; X,=CH. Υ·=Ν, Z*=S 35a: X=CH, Y=S, Z=N; K=CH, r= NH. Z'=N 39a: X=CH. Y=N, Z=S; X'=CH, Υ·=ΝΗ, Z'=N 43a: X=CH, Y=N, Z=S; X' =CH, Yf=S, Z*=N

24a: X=N. Y=0, Z=N; X^CH, Y*=NH, Z^N 28a: X=NY=0, Z=N; X^CH, Y*=S. 2^N 32a: X=N, Y=〇, Z=N; X*=CH, Y*=N, 2*=S 36ft: X=CH, Y=S, Z=N; Χ·=ΟΗ. Y*= NH. Zf=N 40a: X=CH, Y=N, Z=S; Χ*=ΟΗ, Y*=NH, Z*=N 44a: X=CH, Y=N, Z=S; X=CH , Y*=S, Z'=N

37a: X=CH, Y=S, 2=N; X=CH, r=NH, Z=N 4ia: X=CH, Y=N, Z=S; >C=CH, Y'=NH. Z=N 45a: X=CH, Y=N. Z=S; )C=CH. Y.=S, Ζ·=Ν

25a: X=N, Y=〇, Z=N Z9a: X=N, Y=0. Z=N 33a: X=NY=〇. Z=N X'=CH, r=NH, Γ=Ν X .=CH, r=s,z.=N x.=CH.r=N,r=s

R. a a a a a H 2630343842^

Χ=Ν, Υ=0, Ζ=Ν; X'=CH, Υ·=ΝΗ, Γ=Ν χ=Ν, Y=〇t Ζ=Ν; X'=CH, V'=S, Ζ·= Ν Χ=Ν, Υ=0, Ζ=Ν; X*=CH, Υ·=Ν, Z*=S χ=〇Η, Y=S, 2=Ν; X=CH, Υ*=ΝΗ, 2 '=Ν X=CH.Y=N,Z=S; X=CH. Υ·=ΝΗ,Ζ·=Ν χ=〇Η. Y=N, Z=S; X=CH, Y.=S, Z.=NR=R_ = m alkyl, decenyl, heterocycloalkyl or heteroalkenyl 29 201120035 Scheme 12

Boc h _ ή >Boc

23b: X=N, Y=O.Z=N 27b: X=Nf Y=O.Z=N X*CH, Υ·=ΝΗ, 2·=Ν X*=CH, Y.=S, Ζ·=Ν

24b 28b 32b 36b 40b 44b

20b: X*=CH 13b: X*=CH 22b: X*=CH 20b: X*=CH 20b: X,=CH 13b: X*=CH

16b: X=N, Y*〇, Z=N 16b: X=N, Y=0. 2=N 16b: X=N, Y=0, Z=N 12b: X=CH, V=S, Z =N 21b: X=CH, Y=N, Z=S 21b: X=CH, YsN, 2=S

31b: X=N. Y=0, Z=N; X=CH, Y'=N, Z'=S 35b: X=CH, Y=S. Z=N; Χ**ΟΗ, Y*=NH , Z'=N 39b: X=CH, Y=N. Z=S; X^CH, Y'=NH. Z*=N 43b: X=CH, Y=N, 2=S; X^CH, r=S, Z'=N

, Y*=NH,r=N .Y'sS, Z=N ,Y-N,Z'=S Υ·=ΝΗ,Ζ·=Ν Y.=NH.Z.=N

r=s, ZJ=N

X=N, Y=0, Z=N; X'=CH, Y'=NH. Z*=NX=N, Y=0, Z=N; Χ·=ΟΗ, Y'=S, Z*= NX=N, Y=0, 2=N; X=CH, Y'=N. Z*=SX=CH, Y=S. Z=N; X^CH, Y*=NH, 2'=NX= 〇H, Y=N. 2=S; Xf=CH, Y'=NH, Z*=NX=CH, Y=N. Z=S; X'=CH, Y'=S, Z*=N

Boc

F

Boc

25b: X=N, Y=Ot Z=N; X=CH. Υ*=ΝΗ, 2*=N 29b: X=N, Y=0. Z=N; X=CH, Y*=S, Z =N 33b: X=N, Y=0, Z=N; X=CH, V^N, Z'=S 37b: X=CH, Y=S. Z*N; X^CH, Υ'=ΝΗ , ?=Ν 41b: X=CH, Y=N, Z=S; X*=CH, Υ'=ΝΗ( r=N 45b: X=CH, Y=N. Z=S; X*=CH, r=S, 2*=N

O

26b: X»N, Y=0, Z=N 30b: X*N, Y=Ot 2=N 34b: X*N. Y=0,2=N χ·=〇Η, Υ*=ΝΗ, 2 ·=Ν X*=CH, Y'*S, Z*=NX=CH, Y-Ntr*S

38b: X=CH, Y=S, 2=N; X*=CH, Υ·=ΝΗ, Z'=N 42b; X=CH, Y=N, Z=S; X*=CH, Y(= NH, 2*=N 46b: X=CH, Y=N, Z=S; X*=CH. Y'=S. Z*=NR=R'=cycloalkyl.cyclic oxime&, gangrene & · or miscellaneous alkenyl 30 201120035 process 13

16c: Χ=Ν. Υ=0, Ζ=Ν 16c: X=N, Y=0, 2=N 16c: X=N, Y=OtZ=N 12c:X=CH, Y=S, Z=N 21c: X=CH, V=N, 2=S 2Ic: X=CH, Y=N, Z=S

20c: X'=CH, Y'=NH, 2'=N 13c: X'=CH, Y'=SZ=N 22c:X*=CH, Y,=N,Z*=S 2〇c:X .=CH, Υ*=ΝΗ,Ζ·=Ν 20c: Χ·=ΟΗ, Υ·=ΝΗ, Z*=N

13c: X-=CH, Y.=S.Z-=N F

F

23c: X=N, Y=0, Z=N; X*=CH, Υ'=ΝΗ, 2*=N 27c: X=N, Y=0. Z=N; X'sCH, Y*=S , Z'=N 31c: X=N, Y=0, Z=N; X^CK Y'=N, Z^S 35c: X=CH, Y=S, Z=N; X'=CH, Υ ·=ΝΗ, Z'=N 39c: X=CH, Y=N, Z=S; X'CH, Y*=NH, Z'=N 43c: X=CH, Y=N, 2=S; X 'CH, Y*=S, Z=N

24c: X=N, Y=0, Z=N; X*=CH, Y'=NH, Z'=N 28c: X=N. Y=0, Z=N; X*=CH, Y^S Z'=N 32c: X=N. Y=0, Z=N; X*=CH, Y*=N, Z=S 36c: X=CH. Y=S. 2=N; X*=CH , Y*=NH, Z'=N 40c: X=CH, Y=N, Z=S; X*=CH, Y'=NH, Z'=N 44c: X=CH. Y=N. 2= S; X*=CH, Y*=S. Z =N

25c: X=N, Y=0, 2=N; Χ·=ΟΗ, Y^NH. Z'=N 29c: X=N, Y=0, 2=N; Χ·=ΟΗ, Y*=S , Z*=N 33c: X=Nt Y=0, Z=N; X*=CH, Y*=N, Z*=S 37c: X=CH, Y=S, Z=N; X*=CH , Y'=NH, 2*=N 41c: X=CH, V=N, 2=S; X*=CH, r=NH, Z^N 45c: X=CH, Y=N. Z=S; χ·=ΟΗ, r=S, Z*=N

O

R· 26c: X=N, Y=0, 2=N 30c: X=N, Y=〇. Z=N 34c: X=N, Y=0, Z=N

X.=CH, Υ.=ΝΗ,Ζ·=Ν X.=CH, Y_=S. Z.=N χ·=〇Η, Y'=N, Z'=S

38c: X=CH, Y=S, 2-N; X*=CH, Y'^NH, Ζ·=Ν 42c: X=CH, Y=N. Z=S; X*=CH, Y*= NH. 2*=N 46c: X=CH, Y=N, 2=S; X*=CH, Y*=S, Zf=NR=R|=alkyl, cycloalkenyl, heteroalkyl, Or a heterofluorenyl group can also be synthesized using similar procedures as described in Schemes 1 through 13 and modified as deemed necessary by those of ordinary skill in the art. 3 1 201120035 The compounds so synthesized can be purified by flash chromatography, high performance liquid chromatography, crystallization or any other suitable method. The compounds described herein may include several asymmetric centers, such that they are capable of racemates and racemic mixtures, single mirror isomers, individual non-image isomers, non-mirrored/ The inclusions, as well as the cis or trans isomers, exist, so all such isomers are taken into account. Also within the scope of the invention are (1) a pharmaceutical composition comprising an effective amount of any of the compounds of the invention and a pharmaceutically acceptable carrier, and (2) administering an effective amount of such a compound to the treatment. The main Zhao Qi HCV infection treatment. The term "treatment" as used herein refers to the administration of a compound to a subject with or without HCV; {^, or a propensity for the development of such a disease, in order to achieve treatment, cure, alleviate, slow , change, heal, improve, improve, or influence the above-mentioned conditions, their symptoms, or their tendency to develop. The term "effective dose" refers to the amount of active agent required to produce the desired therapeutic effect on the subject being treated. For effective dosages, one of ordinary skill in the art will recognize that it will be based on the route of administration, the use of excipients, and the like. The possibility of the common use of the agents changes. For carrying out the method of the present invention, the above pharmaceutical composition may be administered orally, parenterally, by inhalation, topically, rectally, nasally, sublingually, vaginally, or via an implanted reservoir. Dosing. "Parentera", as used herein, refers to subcutaneous, intradermal, intravenous, intramuscular, intra-articular injection, intra-arterial 32 201120035

Injection, intra-articular injection, intrathoracic injection, intraspinal injection, and intracoronary injection or injection techniques. Disease °P "A sterile injectable composition, such as a sterile injectable aqueous or oily suspension, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as TWeen 80) and suspending agents. The injectable preparation may be a sterile injectable solution or suspended in a non-toxic and non-orally acceptable: release solution or solvent, such as a solution of 1,3-butanediol. The solvent is mannitol, water, Ringer's soluti〇n and isotonic vaporized sodium solution. In addition, the sterile non-volatile oil is a conventional solvent or suspension medium (for example: synthetic single) Glycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can also be used in the preparation of injectables, natural pharmaceutically acceptable oils, such as eucalyptus oil or castor oil, especially its polyoxygen B. The form of the base can also be used for preparation. These oil ester solutions or suspensions may contain long-chain alcohol diluents or dispersants, carboxymethyl cellulose, or similar dispersing agents. Other commonly used surfactants Such as Dingween or Spans, or other similar emulsifiers, or general pharmaceutical manufacturing uses in pharmaceutical-acceptable solid, liquid or other dosage forms of bioavailable enhancers for formulation development purposes. The composition may be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. For example, tablets for oral use are generally used as lactose. Or cornstarch 'lubricants (such as magnesium stearate) are often added to it. In the case of oral capsule administration, available diluents include lactose and dried cornstarch. When used as an aqueous suspension or emulsion When administered, live 33 201120035 Sexual ingredients can be suspended or dissolved in an oily interface mixed with an emulsifier or suspending agent. If necessary, add a moderate amount of sweetener, flavor or pigment. Nasal gasification spray The aerosol or inhalant composition can be prepared according to the known techniques in the field of pharmaceutical dosage forms. The composition containing the compound can also be administered by rectal administration. The composition of the carrier must be pharmaceutically "acceptability", i.e. it must be compatible with the formulation of the active ingredient (preferably based stable active ingredient), and the test can not cause damage to the body being treated. For example, one or more solubilizing agents which form a more soluble complex with the compound can be used as a pharmaceutical carrier for delivering the active compound. Examples of other carriers include colloidal cerium oxide, magnesium stearate, sodium lauryl sulfate and D&amp;C yellow. The above compounds of the present invention can be first screened for their effects in treating the above diseases by in vitro analysis and then confirmed by animal experiments and clinical trials. Other methods are well known to those skilled in the art. The above description of the present invention is intended to be illustrative, and is not intended to be The text is hereby incorporated by reference in its entirety. Example 1: 〇S)-t-butyl 2-(2-(4-bromophenyl)·2-oxoethylaminecarbamyl). Synthesis of W-Boc-l (R-iee-butyl 2-(2-(4-bromopheny 1)-2-ox〇ethylcarbamoyGpyrr〇lidine-l-carboxylate (la)) - a solution of valine (5.16 g, 24.0 mmol) and H0Bt.H20 (3.67 g, 24.0 mmol), stirred at room temperature for 10 min, then N-ethyl &lt;-&gt; Aminopropyl)carbodiimide hydrochloride (1^-6111丫1-]^'- 34 201120035 (3-dimethylaminopropyl)carbodiimide hydrochloride , EDC.HC1, 4.60 g, 24.0 mmol) The mixture was stirred at room temperature for 30 minutes and then treated with a yellow solution which was stirred at room temperature by stirring 2-amino-4'-bromoacetophenone hydrochloride (2_amino-45-bromoacetophenone) Hydrochloride, 5.0 g, 20.0 mmol) was formed with N,N-diisopropylethylamine (DIPEA, 2.58 g, 20 mmol) for 10 min. The mixture was stirred at room temperature overnight. Then, the precipitate was removed by filtration through Celite®, and the filtrate was extracted with dichloromethane and water. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (ethyl acetate: n-hexane = 2: 5) yielded the pure product of the yellow collite la (7.39 g, 90%) ° Example 2: (5*)-t-butyl 2-( 5-(4-bromophenyl)thiazol-2-yl)pyrrolidin-1-one acid vinegar ((^々a'-butyl 2-(5-(4-bromophenyl)thiazol-2-yl)pyrrolidine- The synthesis of l-carboxylate (2a)) was carried out by adding a Lawson reagent (37.21 g, 92.11 mmol) to a tetrahydrofuran solution (THF, 300 ml) of a brewed amine substrate la (25.26 g, 61.42 mmol). The mixture was refluxed for 6 hours, then cooled to EtOAc EtOAc (EtOAc) %) Example 3: 〇S)-Third butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl)thiazol-2-yl)pyrrolidine-1-carboxylic acid ((S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2) - 35 201120035 dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolid-ine-1 -carbox ylate (3a)) The synthesis of Pd(PPh3)4 (0·49 g, 0.43 mmol), acetic acid Potassium (2.09 g, 21.37 mmol) and dipentazone (5.16) g, 17.1 mmol), compound 2a (3.50 g, 8.55 mmol) and 1,4-dioxacin (100 mL) in a reaction flask, filled with nitrogen, and then the reaction mixture was stirred at 80 ° C for 6 hours. After cooling to room temperature, the obtained mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjj 99%). Example 4: (2 brother 23)-di-tert-butyl 2,2·-(5,5·-(biphenyl-4,4·-diyl)bis(thiazole-5,2-diyl)) Dipyrrolidine-1-carboxylate butyl 2,2'-(5,5'-(biphenyl-4,4'-diyl)bis(thiazole-5,2-diy 1)) dipyrrolidine-l-carboxyl-ate (4a)) The synthesis was packed with PdCl2 (dppf) (0.48 g '0.59 mmol), carbonic acid _ (5.87 g, 42.5 mmol), 2a (3.75 g, 9.16 mmol), 3a (3.88 g, 8.5 mmol) and 1 , 2-dimethoxyethane (100 mL) in a reaction flask, filled with nitrogen, and then the reaction mixture was stirred at 80 ° C for 18 hours. After cooling to room temperature, the resulting mixture was filtered, and the filtrate was reduced. Concentration by pressure, the residue was purified by column chromatography (ethyl acetate: n-hexane = 1:1) to yield product 4a (2.66 g, 47%). Example 5: 4,4'-bis(2-((5)-pyrrolidin-2-yl)thiazol-5-yl)biphenyl (4,4·-bis(2-((5*)-pyrrolidin) Synthesis of -2-yl)thiazol-5-yl)biphenyl (5a)) at room temperature, compound 4a (2.66 g '4.04 mmol) of dioxozol 36 201120035 solution was added with trifluoroacetic acid'. After mixing for 2 hours, the mixture was decompressed under reduced pressure to obtain a viscous liquid. The liquid was added to steaming water and a second gas to be calcined, and the resulting mixture was cooled in an ice bath, and saturated sodium hydrogencarbonate was added until pH=8. The mixture was extracted with a methylene chloride (40 mL EtOAc). The residue was purified by flash column chromatography (100% ethyl acetate, then methanol: hexanes: 1:1) to yield pure product 5a (1.83 g, 99%) 〇 Example 6: ?,1,/〇-2,2|-((2\2,5&gt;2,2,-(5,5'-(biphenyl-4,4,-diyl) bis(thiazole-5,2 -diyl)) bis(pyrrolidine-2,1-diyl))bis(2-oxo-N-phenylideneethane-2,1-diyl)diamine decanoate ((1,5,5 '-(biphenyl-4,4'_diyl)bis(thiazole-5,2-diyl))bis(pyrrolidi ne-2,l-diyl))bis(2-oxo-l-phenylethane-2,l-diyl) Synthesis of dicarbamate (6a)) Add all HOBt.H2〇 to a solution of #-Boc-d· stupylglycine (2.21 g, 8.8 mmol) in dimethylformamide (30 ml) at room temperature (1.35 g' 8.8 mmol), the mixture was stirred at room temperature for 1 hr, then ΕΙχ: (1.68 g, 8·8 mmol) was added, and the mixture was stirred for 30 minutes, and compound 5a (1.83 g, 4.0 mm 〇i) bis decylamine (20 ml) solution. The resulting mixture was stirred at room temperature overnight, then extracted with ethyl acetate and water (HOBt salts were removed) and the organic layer dried over magnesium sulfate , filtered and concentrated. Residues Purification by gel column chromatography (methanol: di-methane methane = 1: 20) yielded pure product 6a (2.77 g, 75%) of white solid. Example 7: diyl) double (嗟) sit ·5, 2-Diyl" bis(t-rhodium-2,l-diyl)) bis (2.oxo small 37 201120035 phenylethane-2,1-diyl)dicyclopropanecarbamamine (^AT- (UUW)-2,2i-((25,2 ^)-2,2'-(5,5'-(bipheny 1-4,4'-diyl)bis(thiazole-5,2-diyl) )bis Synthesis of (pyrrolidine-2,l-diyl))bis(2-oxo-l-phenylethane-2,l-diyl)dicyclopropanecarboxamide (7a-A)) at room temperature, compound 6a (2.21 g, 8.8 mmol) Trifluoromethaneamine (25 mL) was added to a solution of trifluoroacetic acid (5 mL), and the mixture was stirred for 2 hrs, then concentrated under reduced pressure. The mixture was extracted with dioxane (20 mL EtOAc). The crude product was used as a starting material for the next step without further purification. The crude THF (20 mL) solution was cooled in ice-bath, and cyclopropanecarbonyl chloride (208 mg, 1.99 mmol) and triethyl The amine (126 mg, 1.24 mmol) was evaporated and evaporated. The residue was extracted with ethyl acetate (10 mL EtOAc)EtOAc. The residue was purified by column chromatography (methanol: m. m. m.): ield. LC/MS (ESI): [M+2]+/2: 431 » [M+l]+: 861 » [M+23]+: 883. Example 8: Synthesis of (5&gt;Third-butyl 2-aminopyridylpyrrolidine-1-carboxylate ((5)-ieri-butyl 2-carbamoylpyrrolidine-l-carboxylate (10a)) #-Boc- L-Proline (5.0 g, 23, 2 mmol) was dissolved in 1,4-dioxin (110 ml) at room temperature, 0 pyridine (1.1 mL, 13.9 mmol), dicarbonate #38 201120035 Di-ieri-butyl dicarbonate '6.6g (30.2 mmol) and carbonic acid (2.9 g, 30.2 mmol) were added to the proline solution, and the reaction mixture was stirred at room temperature for 19 hours. The volatile component was removed by evaporation under reduced pressure, and ethyl acetate (5 mL), 20% aqueous citric acid and brine (50ml) mixture was added to the residue. The mixture was stirred at room temperature for 5 minutes, and the aqueous layer was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered, and then evaporated to give the crude product < </ RTI> then the crude product was purified by column chromatography (di methane:methanol = 9:1) to yield 10a (4.5 g). 9 : (*S&gt; Preparation of the preparation of (S)-tert-butyl 2-carbamothioylpyrrolidine-l-carboxylate (11a) Have Tributyl 2-amine-mercaptopyrrolidine-1-carboxylate (Compound 10a, 3.0 g, 14.0 mmol) and Lawson's reagent (6.8 g, 16.8 mmol) in a round bottom flask filled with nitrogen and added anhydrous THF (40 ml) was used as a solvent, and the reaction mixture was stirred under a nitrogen atmosphere at 70 ° C for 8 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography (ethyl acetate: n-hexane) =1 : 2) Purification, yielding pure product 11a (2.7 g). Example 10: 〇S)-T-butyl 2-(4-(4-bromophenyl)thiazol-2-yl)咐• Preparation of (S)-third of "S^-ieri-butyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-l-carboxylate (12a)) Butyl 2-thioaminemethopyryrrolidine-1-carboxylate (Compound 11a, 2.2 g, 9.6 mmol) and 4-bromophenacyl bromide (2.9 g, 10.5 mmol) Ethanol (5 〇 ml) 39 201120035 The solution was stirred at room temperature for 3 hours, and the obtained mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and then evaporated. Column chromatography (ethyl acetate: n-hexane = 1: 3) pure , Can produce pure product 12a (3.3 g). Example 11: 〇S)-t-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (thiazol-2-yl)pyrrolidine-1-carboxylate ((S)-tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan) Preparation of -2-yl)phenyl)thiazol-2-yl)pyrrolidine-l-carboxylate (13a)) was filled with dipentane diboron (1.1 g, 4.4 mmol), Pd(PPh3)4 (0.13 g, 0.11 mmol) and K2C〇3 (1.5 g, 11.0 mmol) in a round bottom flask, filled with nitrogen at room temperature, then added 〇S)-t-butyl 2-(4-(4-bromophenyl) thiophene嗤-2-base). A solution of piroxicam-1-resin vinegar (compound 12a, 1.5 g, 3.7 mmol) in DMSO (20 mL) was stirred at 80 ° C overnight. After cooling to room temperature, the mixture was obtained ethyl acetate. /h2o extraction, dried over magnesium sulfate, filtered and concentrated to give a yellow liquid. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 1: 5) to yield product 13a (1.1 g) as white solid. . Example 12: Preparation of 4-bromo-V-hydroxybenzamide (15)) 4-Bromobenzonitrile (5.0 g, 27.5 mmol) of ethanol ( In a solution of 42 ml), hydroxylamine hydrochloride (1.91 g, 27.5 mmol) and DIPEA (4.8 m b 27.5 mmol) were added at room temperature, and the reaction mixture was stirred at 90 ° C for 5 hours until 40 201120035 After cooling to room temperature, the obtained mixture was concentrated to give a colorless liquid. The mixture was evaporated to ethyl ether. 15 (5.0 g). Example 13: (5&gt;Third butyl 2-(3-(4-bromophenyl)-1,2,4-oxadiazole _5·yl)°Heptide-1-acidate (( Preparation of S^-ieri-butyl 2-(3-(4-bromo-phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-l-carboxylate (lh)) in WBoc-L-proline (2.5 g, 11.6111111〇1) of 1^,&gt;1-dimethyl indenosamine (#,#-£1111^11&gt;^〇1&gt;111&11^ &lt;16,18 1111^) solution, (9-(benzotriazol-1-yl)tetramethyluronium tetrafluoroborate (0-(66112 〇132〇1-l-yl)-Ar, Ar, Ar, Ar, -tetramethyluronium tetrafluoroborate ' TBTU, 3.73 g, 11.6 mmol), HOBt.H2 〇 (0.36 g, 2.32 mmol) and DIPEA (10.2 ml, 58.1 mmol), the reaction mixture was stirred at room temperature After 5 minutes, 4-bromo-#.hydroxyphenylhydrazine 15 (2.5 g, 11.6 mmol) was further added, and the mixture was stirred at 110 ° C for 2.5 hours. After cooling to room temperature, the obtained reaction mixture was ethyl acetate. After extraction, it is dried over magnesium sulfate, filtered and concentrated to give a crude yellow liquid, which is purified by column chromatography (ethyl acetate: n-hexane = 1: 10) to yield the desired product 16a (2.5 g Example 14: (5&gt;Third butyl 2-(2-(4-bromophenyl)-2-oxoethylaminemethyl)°Bilo bite-1 - rancid brewing 2-(2) -(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-l-carboxylate (18a)) was prepared from 2-amino-4'-oxaphenidate hydrochloride 17 (2-amino-4'-bromo- 41 201120035 acetophenone hydrochloride, 5.0 g, 20.0 mmol) of a gas-fired (150 mL) suspension In the solution, DIPEA (2.6 g, 20 mmol) was added at room temperature, and after stirring for 10 minutes, the suspension became a yellow solution. Hydrazine acid (5.2 g, 24.0 mmol) was charged with dioxane (100 mL). To the solution, H0Bt-H20 (3.7 g, 24.0 mmol) was added at room temperature, and EDOHC1 (4.6 g, 24.0 mmol) was added to the mixture. The mixture was stirred at room temperature for 30 minutes. The solution was added to the lysine mixture and stirred at room temperature overnight. The resulting mixture was filtered through Celite® to remove the precipitate. The filtrate was extracted with water and dioxane, and the organic layer was washed with water. The residue was purified by column chromatography (ethyl acetate: n-hexane = 2: 5) to yield purified product of product 18a (7.4 g). : (5&gt;Third butyl 2-(5-(4-bromophenylimidazol-2-yl)° 洛洛 bit-1-retalic acid ((*S)-ieri-butyl 2-(5-( Preparation of 4-bromopheny 1)-1//-imidazol-2-yl)pyrrolidine-l-carboxylate (19a)) in tert-butyl 2-(2-(4-bromophenyl)-2-oxoethyl Aminoguanidine) 0 洛洛-1--1- vinegar (compound 18a) 5.0 g, 12.2 mmol) in xylene (75 ml), add ammonium acetate (23.4 g, 304 mmol) and acetic acid (5 ml) at room temperature. The reaction mixture was placed in an oil bath with water (to do The mixture was heated to 160 ° C in a Dean-Stark apparatus. After 3 hours, the resulting mixture was cooled to room temperature, then extracted with ethyl acetate and distilled water. After concentration under reduced pressure, a crude material was obtained which was purified by column chromatography (100% ethyl acetate) to yield the product 19a (4.4 g). Example 16: 〇S)-Third butyl 2-(5-(4-(4,4,5,5-tetradecyl-1,3,2-di 42 201120035 oxyborolan-2-yl) Phenyl)-1//-imidazol-2-yl)pyrrolidine-1-carboxylate ((幻-ieri-butyl 2-(5-(4-(4,4,5,5-tetramethyl-l) , 3,2-dioxaborolan-2-yl)pheny 1)-l//-imidazol-2-yl)pyrrolidine-l-carboxylate (20a)) was prepared with dipentane diboron (0.8 g, 3.2 mmol) ), Pd(PPh3)4 (0.06 g '0.05 mmol) and potassium acetate (0.37 g, 3.81 mmol) in a round bottom flask, filled with nitrogen at room temperature, then added (S)-t-butyl 2-( 5-(4-Bromophenyl)-1//-imidazol-2-ylpyrrolidin-1-carboxylate (Compound 19a, 0.5 g, 1.3 mmol) 1,4-dioxane (15 mL) The solution and the reaction mixture were stirred at 80 ° C overnight and then cooled to room temperature. The obtained mixture was extracted with ethyl acetate and distilled water, and the organic layer was dried over magnesium sulfate. It was purified by column chromatography (ethyl acetate: n-hexane = 2:1) to yield product 20a (0.53 g) as a white solid. Example 17: (S)-T-butyl 2-(5- (4-Bromophenyl)thiazol-2-yl). The preparation of compound 21a is similar to the preparation of (S)-ieri-butyl 2-(5-(4-bromophenyl)thiazol-2-yl) pyrrolidine-l-carboxylate (21a)). The method described in Example 2. Example 18: 〇S)-Third butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolane) -2-yl)phenyl) sigh. Sit _2_base) "Beilo bite-i_ tacroleate ((^)-ieri-butyl 2-(5&gt;(4-(4,4,5, Preparation of 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolidine-1 -carboxyate (22a)) Compound 43 was prepared from compound 21a in a similar manner to that described in Example 3. 201120035 22a » Example 19: 〇S)-Third butyl 2-(4-(4'-(5-((S)-l_(T-butoxycarbonyl))) 1,2,4-Ming bis-β-yl-3-yl)biphenyl-4-yl-1//--salt-2-yl) &lt;5)-Chemical 15117172-(4-(4'-(5-((8)-1-(161*1;-butoxycarbonyl)pyrrolidin-2-yl)-l,2,4-oxadiazol-3 -yl)biphen y 1-4-y 1)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (23a)) was prepared by filling with PdCl 2 (dppf) (0,04 g, 0.051 mmol), Sodium bicarbonate (0.37 g' 4.45 mmol) and 〇S)-t-butyl 2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1 - a reaction flask of the carboxylate (compound 16a, 0.50 g, 1.27 mmol), filled with nitrogen, then added (*S)-t-butyl 2-(5-(4-(4,4,5,5) -tetradecyl·1,3,2·dioxaborolan-2-yl)phenyl)-1//-imidazol-2-yl)pyrrolidine-1-carboxylate (compound 20a, 0.67 g, 1.52 mmol) of 1,2-dimethoxyethane (15 ml), the reaction mixture was stirred at 8 ° C for 6 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate / water. After drying with MgSO4, EtOAc (EtOAc):EtOAc Example 20: 5-(〇S)-pyrrolidin-2-yl)-3-(442-(0 pyrrolidin-2-yl-//-imidazol-4-yl)biphenyl-4-yl-l , 2,4-oxadiazole (5-((*S)pyrroli &lt;iin-2· yl)-3-(4'-(2-((S)-pyΓrolidin-2-yl)-J^-imiciazol-4-yl)biphenyl •4-yl)-l,2, Preparation of 4-oxadiazole (24a)) In a similar manner to that described in Example 5, compound 44 was prepared from compound 23a. 201120035 24a 0 Example 21: Compound 2 5a was prepared at a temperature, W-Boc-D-phenylgan Add a total of H0Bt.H20 (0_18 g' 1.15 mmol) to a solution of the amine acid (0.29 g, 1.15 mmol) in dioxane (10 mL). The mixture was stirred at room temperature for 1 min. 0.22 g ' 1.15 mmol), after 10 minutes 'add all 5-((5)-°piridin-2-yl)-3-(4'-(2-((S)-pyrrolidine-2) -yl-///-imidazol-4-yl)biphenyl-4-yl-1,2,4-oxadiazole (compound 24a, 0.20 g, 0-48 mmol). After stirring at room temperature overnight, Add 10% citric acid (aqueous solution), and then the mixture is stirred for 10 minutes. The reaction mixture is adjusted to a pH of about 8 s with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate. After concentration, a crude yellow liquid was obtained which was purified by column chromatography (ethyl acetate: n-hexane = 2:1). The product 25a (0.37 g) of the white solid can be obtained. Example 22: ΑΚ(Λ)-2-((5&gt;2-(4-(4,-(5-((')))) /?)-2-(cyclopropanecarbamimidino)-2-phenylethenyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4- Base)-///-imidazol-2-yl)n-pyridin-1-yl)-2-oxo-1-phenylethyl)cyclopropanecarbamamine (#-((幻-2-( 〇5)-2-(4(4-(4'-(5-(())) (cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1,2,4-oxadiazol Benzylpropylidene Compound 45 was prepared from compound 25a in a manner similar to that described in Example 7 201120035 26a ° Example 23 : ( &lt;S)-Tertiary Butyl 2-(4-(4,-(5-(〇S)-1-(Tertidinoxycarbonyl)pyrrolidin-2-yl)-1,2,4-Evil Diazol-3-yl)biphenyl-4-yl)thiazol-2-ylpyrrolidin-1-carboxylate (OS)-ieri-butyl 2-(4-(4,-(5-((S) )-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-l,2,4-oxadiazol-3-yl)biphen yl-4-yl)thiazol-2-yl)pyrrolidine-l-carboxylate (27a)) The preparation of Compound 27a was carried out in a similar manner to that described in Example 4 except that Compounds 13a and 16a were used instead of Compounds 2a and 3a. Example 24: 5-(〇S)-pyrrolidin-2-yl)-3-(4,-(2-(〇S)-pyrrolidin-2-yl)thiazol-4-yl)biphenyl-4 -yl)-1,2,4-,:i(5-(〇S)-pyrrolidin-2·yl)-3-(4'-(2-((5)-pyrrolidin-2-yl)thiazol- Preparation of 4-yl)biphenyl-4-yl)-l,2-oxadiazole (28a)) Compound 28a was prepared from compound 27a using the procedure described in Example 5, using the product as starting material for the next step. No further purification is required. Example 25: Preparation of compound 29a Compound 29a was prepared from compound 28a in a procedure analogous to that described in Example 21 Example 26: ((8)-2-(〇S&gt; 2-(4-(4,-(5-) (〇S)-1-((8)-2-(cyclopropanecartosyl)-2-phenylethyl). Bilo bite_2_yl)-1,2,4-. 3-yl)biphenyl-4-yl)-thiazol-2-yl)"pyrrolidin-1-yl)-2-oxo-1-indolylethyl)cyclopropanecarboxamide (AM(/ 〇-2-(( &lt;S)-2-(4-(4,-(5-((S)-l-((/?)-2- 46 201120035 (cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-1 -yl)-2-oxo-l-phenylethyl)cyclopropanecarboxamide (30a))-^ Prepared at room temperature Trifluoroacetic acid (5 mL) was added to a solution of compound 29a (0.20 g, 0.22 mmol), and the mixture was stirred for 2 hr. The resulting mixture was extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was used as a starting material for the next step without further purification. Add a total of cyclopropanecarbonyl chloride '0.058 g, 0.55 mmol) and triethylamine (0.08 ml) to a white solid in dioxane (5 ml) at -10 °C. The combined solution was stirred at -10 ° C for 15 minutes, distilled water was added at room temperature, and then extracted with di-methane. The organic layer was dried over MgSO4, filtered and evaporated tolululululululululululululululululululululu Example 27: 〇S)-t-butyl 2-(5-(4'-(5-((S)-l-(t-butoxycarbonyl)pyrrolidin-2-yl)-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)° than bite-1-carboxylate (OS^-ieri-butyl 2-(5-(4'-( 5-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphen yl-4-yl)thiazol-2-yl)pyrrolidine-l- Preparation of Compound 31a of Carboxylate (31a)) The procedure described in Example 4 was followed except that Compounds 16a and 22a were used in place of Compounds 2a and 3a. 47 201120035 Example 28: 5-(( &lt;S)-e than butyl-2-yl)-3-(4'-(2-((iS)-° than hexane-2-yl) oxime-5-yl)biphenyl-4- Base)-1,2,4-° dioxin (5-((5')-pyrrolidin-2-yl)-3-(4,-(2-((S)-pyrrolidin-2-yl)) Preparation of thiazol-5-yl)biphenyl-4-yl)-l,2-oxadiazole (32a)) Compound 32a was prepared from compound 31a in a procedure analogous to that described in Example 5, using the product as a subsequent step. The starting material was obtained without further purification. Example 29: Preparation of compound 33a Compound 33a was prepared from compound 32a in a procedure similar to that described in Example 21. Example 30: AK(i〇-2-(〇S)-2-(5-(4'-(5-(〇S)-1-((幻--2-)cyclopropanoyl)- 2-Phenylethenyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)-thiazol-2-yl)pyrrolidin-1-yl )-2-oxo-1-phenylethyl)cyclopropane decylamine (#-((/0-2-((5)-2-(5-(4^-(5-((5))) -1-((/0-2-(cyclopropanecarboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-l,2,4-oxadiazol-3-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin Preparation of -l-yl)-2-oxo-l-phenylethyl)cyclopropanecarboxamide (34a)) Compound 34a was prepared from compound 33a in a procedure similar to that described in Example 26. Example 31: (5 &gt; (4-(4·-(2-(〇5)-1-(Tertidinoxycarbonyl)pyrrolidin-2-yl)-/open-imidazole-5-yl)biphenyl-4-yl)thiazole- 2-base) °pyrrolidine-1-acid vinegar ((5')-ieri-butyl 2-(4-(4'-(2-((5)-1-(ieri- 48 201120035 butoxycarbonyl)pyrrolidin The preparation of -2-yl)-7i/-imidazol-5-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidine-l-carboxylate (35a)) was filled with compound 12a (0.46 g, 1.13 mmol), (*S)-Third butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Cyclo-2-yl)phenyl)-1//-imidazole-2·yl)pyrrolidine-i-carboxylate (compound 2〇a, 0.55 g, 1.25 mmol), PdCl 2 (dppf) (〇.036 g) , 0.04 mmol) and sodium bicarbonate (0.33 g ' 3.93 mmol) in a flask, after filling with nitrogen, 1 &gt; 2 - dimethoxyethane (6 ml) and distilled water (2 ml) were added as a solvent. The mixture was stirred under a nitrogen atmosphere at 8 ° C for 5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate / water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The compound was purified by column chromatography (ethyl acetate: n-hexane = 4 ················································ -4-(4,·(2-((5)-pyrrolidin-2-ylimidazol-5-yl)biphenyl-4-yl)thiazole (2_((7)_pyrr〇lidin_2· yl)-4-(4, -(2-((5)-pyrrolidin-2-yl).7//.imidazol.5.yi)biphenyl-4-yl)thiazole (36a)) was prepared in a similar manner to that described in Example 5 by compound Compound 36a was prepared as 35a using the product as the starting material for the next step without further purification. Example 33: Preparation of compound 37a A solution of AMBoc-d-phenylglycine (〇37 g '〇15 mm〇1) in N,N-dimethylformamide (8 mL) at room temperature Add all H〇Bt.H2〇 (0.25 g, 1.63 mmol)' After stirring the mixture for 15 minutes, add all EDC (0.31 g, 1.63 _〇1) and 2_((7) pyrrolidine_2_49 201120035 base) -4-(4'-(2-(〇S)-°pyrrolidine·2_yl)_/good_imidazole·5·yl)biphenyl_4•yl)thiazole (Compound 36a, 0.30 g, 0.68 Mm〇1). After stirring overnight, the obtained mixture was extracted with ethyl acetate and dried over magnesium sulfate. After filtration, the crude product was obtained, and the crude product was purified by column chromatography (ethyl acetate: n-hexane = 2:1). Product 37a (0.42 g) was obtained as a white solid. Example 34: #-((70-2-((5)-2-(4-(4)(2-((5)-1-(())))) -2-phenylethenyl)pyrrolidinyl-2-yl)-ih-imidazol-5-yl)biphenyl-4-yl)-thiazol-2-yl).pyrrolidin-1-yl)-2- Oxo-1-phenylethyl)cyclopropane 曱carboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-lH-imidazol-5-yl)biphenyl-4-yl)thiazol-2-yl)pyrrolidin-l Preparation of -yl)-2-oxo-l-phe nylethyl)cyclopropanecarboxamide (38a)) Compound 38a was prepared from compound 37a in a procedure similar to that described in Example 26. Example 35: (61)-Third-butyl 2-(5-(4'-(2-((5))-1-(t-butoxy)pyrrolidin-2-yl)-7/ /-imidazole-4.yl)biphenyl-4-yl)thiazol-2-ylpyrrolidin-1-carboxylate (〇SHeri-butyl 2-(5-(4^(2-((5). ^^6^. butoxycarbonyl)pyrrolidin-2-yl)-i//-iniidazol-4-yl)biphenyl- 4-yl)thiazol-2-yl)pyrrolidine-bucarboxylate (39a)) Preparation of Compound 39a The procedure described in Example 4 was followed except that compounds 20a and 21a were used in place of compounds 2a and 3a. Example 36: 2-(〇S)-°bipyridin-2-yl)-5-(4'-(2-((5)·°pyrrolidine-2-50 201120035 base)-/// -imidazol-4-yl)biphenyl-4-yl)thiazole (2-((S))-pyrrolidin-2-yl)-5-(4,-(2-((5)-pyrrolidin-2-) Preparation of yl)-7//-im idazol-4-yl)biphenyl- 4-yl)thiazole (40a)) In a similar manner to that described in Example 5, compound 40a was prepared from compound 39a using the product as a subsequent step. The starting material was obtained without further purification. Example 37: Preparation of compound 41a In a solution of 'iV-Boc_D-phenylglycine (0.14 g, 0.56 mmol) in dimethylformamide (5 ml) at room temperature, all H0Bt.H20 ( 0.086 g, 0.56 mmol) 'The mixture was stirred for 1 min, then Et) C (0.11 g, 0.56 mmol) was added. The mixture was stirred for 30 minutes, adding all 2-((5)-° ratio slightly bite -2-yl)-5-(4.-(2-((5)-°Bilo-2-yl)-/)---m--4-yl)biphenyl-4·yl)° &quot;Sit (Compound 40a, 0.10 g, 0.23 mmol), and the mixture was stirred at room temperature overnight. After the HOBt was washed with distilled water, the obtained mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography (ethyl acetate: n-hexane = 1: 1) Purified to yield the product 41a (0.072 g) as a white solid. Example 38. ((and)-2-((*5)-2-(5-(4'-(2-?())-1-((/?)-2-) Brewed amino)-2-phenylethyl) &lt;»Bilo bit-2-yl)-///-»Miso-4-yl)biphenyl-4-yl)-thiazol-2-yl)pyrrolidin-1.yl)-2-oxo -1-phenylethyl)cyclopropane decylamine (#-((/?)-2-((51)-2-(5-(4|-(2-((*$1)-1-) (/?)-2-(〇丫.1〇卩1&gt;〇卩3116-carboxamido)-2-phenylacetyl)pyrrolidin-2-yl)-7//-imidazol-4-yl)biphenyl-4-yl) Preparation of thiazol-2-yl)pyrrolidin-l-yl)-2-oxo-l-phe nyl-ethyl)cyclopropanecarboxamide (42a)) 51 201120035 Compound 41a (0.072 g, 0.08 mmol) of dimethyl at room temperature Trifluoroacetic acid (1 mL) was added to the solution of the decylamine (2 ml), and the mixture was stirred for 2 hr, and saturated sodium bicarbonate was added to adjust the pH to about 8. The resulting mixture was extracted with dioxane, dried over magnesium sulfate, filtered and concentrated. The crude product was used as a starting material for the next step without further purification. To a solution of the above white solid in THF (20 mL), EtOAc (EtOAc: EtOAc (EtOAc) Stir at ° C for 2 hours. After the solvent was removed, the crude product was purified by column chromatography (methanol: ethyl acetate = 1 : 40) to afford product 42a (0.033 g) as white solid. Example 39: 〇S)-Third butyl 2-(5-(4匕(2-(〇S&gt;l-(T-butoxycarbonyl)))) Base) biphenyl-4 -yl) 嗟β sit-2-yl)D 洛洛 bit-1 - slow acid vinegar ((iS^-ieri-butyl 2-(5-(4'-(2-((5 ·)-1-(ίβ, ί-1»ιιί;οχγεαΓΐ3〇ηγ1) pyrrolidin-2-yl)thiazol-4-yl)biphenyl-4-yl)thiazol-2-yl)pyrro lidine-l-carboxylate (43a Preparation of Compound 43a was carried out in a similar manner to that described in Example 4 except that Compounds 13a and 21a were used in place of Compounds 2a and 3a. Example 40 (5 &gt; 4,5'-(biphenyl-4, 4'-diyl)dibipyridin-2-yl)=3⁄4 ((5)-4,5'-(biphenyl-4,4'-diyl)bis(2-((5,)-pyrrolidin-2 -yl) thiazole) (44a)) Preparation Compound 44a was prepared from compound 43a in a procedure similar to that described in Example 5, using product as starting material for the next step without further purification. 52 201120035 Example 41: Compound 4Sa Preparation of compound 45a from compound 44a in a procedure analogous to that described in Example 21. Example 42: ((/0-2-((5)-2-(5-(41-(2-)) 1-((/0-2-(cyclopropane曱醯amino)-2-phenylethenyl)1 1-pyrrolidin-2-yl)thiazol-4-yl)biphenyl-4-yl)-thiazol-2-ylpyrrolidin-1-yl)-2-oxo-indole-phenylethyl) ring Propane meglumine (#-((/^)-2-((5^-2-(5-(4^(2-((5). i-(())_2_(Cycl〇propanecarbox amido)- 2-phenylacetyl)pyrr〇lidin_2-yl)thiazol-4-yl)biphenyl -4-yl)thiazol-2-yl)pyrrolidin-1-yl).2-oxo-l-phenylethyl)cycl opropanecarboxamide (46a)) Preparation of Compound 46a from Compound 45a in a procedure analogous to Example 26. Example 43: Compound 47 bromo (1.3 mL, 25.0 mmol) in EtOAc (15 mL) - a solution of 4,4'-diacetylbiphenyl (3.0 g, 12-5 mmol) in acetic acid (40 mL). After the addition, the reaction mixture was stirred at room temperature overnight. The precipitate was filtered and recrystallized by gas to obtain a white solid, Γ-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) 47 (1,1'-(1^?1) ^1^1-4,4'-diyl)bis(2-bromoethanone), 3.84 g, 77.5%). LC/MS (ESI): [M+l]+: 397. Example 44: Compound 48 Sodium diformylamide (3.66 g, 38.5 mmol) 53 201120035 Added 1, Γ-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) 47 ( 6.1 g, l5·4 mmol) in acetonitrile (85 mL), the reaction mixture was refluxed for 4 hr, then concentrated under reduced pressure, and the residue was suspended in 5% EtOAc (300 mL) . After the reaction mixture was cooled to room temperature and placed in a freezer for 1 hour, the precipitate was collected, washed with diethyl ether (200 mL×3), and dried in vacuo to give 1,1'-(biphenyl-4,4'-diyl) (2-aminoethyl ketone) dihydrochloride 48 (1,1'-(biphenyl-4,4,-diyl)bis(2-aminoethanone) dihydrochloride » 4.85 g, 92%). LC/MS (ESI): [M+l]+: 269. Example 45: Compound 49a to 1,1'-(biphenyl-4,4'-diyl)bis(2-aminoethyl ketone) dihydrochloride 48 (0.7 g, 2.1 mmol), valine ( 0.9 g, 4.2 mmol) and HATU (1.68 g, 4.4 mmol) in dimercaptoamine (15 mL), diisopropylethylamine (1.5 mL) was added dropwise over 5 minutes. The mixture was stirred at room temperature overnight and then concentrated. The residue was extracted with 20% methanol/gas and water, and the aqueous phase was washed once with 20% methanol/methanol. The organic layer was collected and washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, using 10-50% ethyl acetate / dioxane as gradient elution to give product 49a (0.97 g, 69%) ° LC/MS (ESI) ) : [M+l]+ : 663. Example 46: Compounds 50a and 51a Trifluoroacetic acid (1 mL) was added to a solution of compound 6a (462 mg, 0.5 mmol) in hexanes (5 54 201120035 mL) at room temperature, then reacted at room temperature Mix for 2 hours. After the reaction was completed, the ice bath was cooled and saturated sodium hydrogencarbonate was added until pH = 7 to 8. The resulting mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The THF (5 ml) solution of the crude product was cooled in an ice bath, and then acetyl chloride (94 mg, 1.2 mmol) and triethylamine (121 mg, 1.2 mmol) were added to the mixture. The solution was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The residue was extracted with ethyl acetate (10 mL EtOAc). EtOAc (EtOAc)EtOAc. Purification gave the final product 50a (160 mg, 40%) and 51a (50 mg &lt; LC/MS (ESI): [M+2]+/2: 405, [M+l]+: 809 s [M+23]+: 831. Example 47: Compounds 52a and 53a Compounds 52a and 53a were prepared in the same manner as in Example 46 except that propionyl chloride was used in place of acetamidine. LC/MS (ESI): [M+2]+/2: 419 » [M+l]+: 837 &gt; [M+23]+: 859. Example 48: Compounds 54a and 55a Compounds 54a and 55a were prepared in the same manner as described in Example 46 except that butyryl chloride was used in place of ethylene. LC/MS (ESI): [M+2]+/2: 433,[M+l]+: 865,[M+23]+: 55 201120035 887. Example 49: Compounds 56a and 57a Compounds 56a and 57a were prepared in the same manner as described in Example 46 except that pentanoyl chloride was used in place of the enzyme. LC/MS (ESI): [M+2]+/2: 447 » [M+l]+: 893 « [M+23]+ : 915. Example 50: Compounds 58a and 59a Compounds 58a and 59a were prepared in the same manner as described in Example 46 except that hexanonyl chloride was used in place of ethylene gas. 0 LC/MS (ESI): [M+ 2]+/2 : 461 &gt; [M+l]+ : 921 » [M+23]+ : 943. Example 51: Compounds 60a and 61a Compounds 60a and 61a were prepared in the same manner as in Example 46 except that isobutyryl chloride was used in place of ethylene. LC/MS (ESI): [M+2]+/2: 433,[M+l]+: 865,[M+23]+: 887. Example 52: Compounds 62a and 63a Compounds 62a and 63a were prepared in the same manner as in Example 46 except that 2-ethyl-butyryl chloride was used in place of ethylene. LC/MS (ESI): [M+2]+/2: 461 &gt; [M+l]+: 921 « [M+23]+: 56 201120035 943 ° Example 53: Compounds 64a and 65a Compound 64a and 65a was prepared in the same manner as in Example 46 except that 2,2-dimethyl propionyl chloride was used in place of ethyl chloroform. LC/MS (ESI): [M+2]+/2: 447 « [M+l]+ : 893 « [M+23]+ : 915. Example 54: Compounds 66a and 67a Compounds 66a and 67a were prepared in the same manner as in Example 46 except that cyclobutane carbonyl chloride was used in place of ethylene. LC/MS (ESI): [M+2]+/2: 445,[M+l]+: 889,[M+23]+: 911. Example 55: Compounds 68a and 69a Compounds 68a and 69a were prepared in the same manner as described in Example 46 except that cyclopentane carbonyl chloride was used in place of acetamidine. LC/MS (ESI): [M+2]+/2: 459 &gt; [M+l]+ : 917 « [M+23]+ : 939. Example 56: Compounds 70a and 71a Compounds 70a and 71a were prepared in the same manner as in Example 46 except that, in addition to ethylene oxide, cyclohexane carbonyl chloride was used in addition to 201120035. LC/MS (ESI): [M+2]+/2: 473 » [M+l]+: 945 » [M+23]+: 967. Example 57: Compounds 72a and 73a Compounds 72a and 73a were prepared in the same manner as described in Example 46 except that benzoyl chloride was used in place of acetonitrile. LC/MS (ESI): [M +2]+/2 : 467,[M+l]+ : 933,[M+23]+ : 955 » Example 58: Compound 74a and *7Sa Compounds 74a and 75a were prepared in the same manner as in Example 46. But in addition to the use of phenylacetyl chloride instead of acetamidine. LC/MS (ESI): [M+2]+/2: 481: [M+l]+: 961 &gt; [M+23]+: 983 » Example 59: Compounds 76a and 77a Compounds 76a and 77a The process was the same as that described in Example 46 except that acetamethylene was replaced with furan-2-carbonyl chloride. LC/MS (ESI): [M+2]+/2: 457,[M+l]+: 913,[M+23]+: 935. Example 60: Compounds 78a and 79a S8 201120035 Compounds 78a and 79a were prepared in the same manner as in Example 46 except that the use of furan-3-carbonyl chloride instead of ethyl hydrazine was used. . LC/MS (ESI): [M+2]+/2: 457 &gt; [M+l]+ : 913 « [M+23]+ : 935. Example 61: Compounds 80a and 81a Compounds 80a and 81a were prepared in the same manner as in Example 46 except that thiophene-2-carbonyl chloride was used in place of acetamidine. LC/MS (ESI): [M+2]+/2: 473 s [M+l]+: 945,[M+23]+: 967. Example 62: Compounds 82a and 83a Compounds 82a and 83a were prepared in the same manner as described in Example 46 except that thiophene-3-carbonyl chloride was used in place of ethylene. LC/MS (ESI): [M+2]+/2: 473: [M+l]+: 945 &gt; [M+23]+: 967 » Example 63: Compounds 84a and 85a Compounds 84a and 85a The method was the same as that described in Example 46 except that the use of isocotinyl chloride instead of ethylene was used. LC/MS (ESI): [M+2]+/2: 468 &gt; [M+l]+: 935 &gt; [M+23]+: 59 957. 201120035 Example 64: Compounds 86a and 87a Compounds 86a and 87a were prepared in the same manner as described in Example 46 except that they were used in the case of nicotinoyl chloride in place of ethylene. LC/MS (ESI): [M+2]+/2: 468,[M+l]+: 935,[M+23]+: 957. Example 65: Compounds 88a and 89a Compounds 88a and 89a were prepared in the same manner as described in Example 46 except that acetonitrile was replaced with pyridine-2-carbonyl chloride. LC/MS (ESI): [M+2]+/2: 468,[M+l]+: 935,[M+23]+: 957. Example 66: Compounds 90a and 91a Compounds 90a and 91a were prepared in the same manner as described in Example 46 except that pyrroHdine-bcarbony1 chloride was used instead of ethyl hydrazine. LC/MS (ESI): [M+2]+/2: 460 &gt; [M+l]+ : 919 « [M+23]+ : 941. Example 67: Compound 92a Compound 92a was prepared in the same manner as in Example 46 except that piperidine-l-carbonyl chloride was used in place of acetonitrile 201120035 LC/MS (ESI): [M+2]+/2 : 474,[M+l]+ : 947 ' [M+23]+ : 969. Example 68: Compound 95a In a solution of methoxycarbonyl-D-proline (/V~methoxycarbonyl-ci-valine, 420 mg, 2.4 mmol) in dioxane (10 mL), all H0Bt_H20 ( After stirring at room temperature for 10 minutes, EDC (460 mg '2.4 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes, then compound 5a (458 mg, 1.0 mmol) was added. A solution of dioxin &gt; (5 mL) was then stirred at room temperature overnight. After the HOBt is washed with distilled water, the organic layer is dried over magnesium sulfate, filtered and concentrated to obtain a yellow mucus, which is purified by silica gel column chromatography (sterol: dichloromethane = 1: 20) to yield white. Solid 95a (425 mg, 55%). LC/MS (ESI): [M+2]+/2: 387 * [M+l]+: 773 « [M+23]+: 795. Example 69: Compound 96a Compound 96a was prepared in the same manner as described in Example 68 except that methoxycarbonyl-D- was substituted for ethoxycarbonyl-D-valine. In addition to proline. LC/MS (ESI): [M+2]+/2: 401 « [M+l]+ : 801 » [M+23]+ : 823. Example 70: Compound 97a 61 201120035 Compound 97a was prepared in the same manner as described in Example 68 except that iV-phenoxycarbonyl-D-valine was used instead of methoxyl. In addition to carbonyl-D-proline. LC/MS (ESI): [M+2]+/2: 449, [M+l]+: 897,[M+23]+: 919. Example 71: Compound 98a Compound 98a was prepared in the same manner as described in Example 68 except that the methoxycarbonyl-D- group was substituted with iV-cyclopropanecarbonyl-D-alanine. In addition to proline. LC/MS (ESI): [M+2]+/2: 369 » [M+l]+: 737 &gt; [M+23]+: 759. Example 72: Compound 99a Compound 99a was prepared in the same manner as described in Example 68 except that (/2)-2-(cyclopropionyl-amino)-butyric acid ((i?)-2- (cyclopropane-carbonyl-amino)-butyric acid) is substituted for AT-methoxyl-D-lysine. LC/MS (ESI): [M+2]+/2: 383 &gt; [M+l]+: 765 » [M+23]+: 787. Example 73: Compound 100a Compound l〇〇a was prepared in the same manner as in Example 68 except that (Λ)-2-(cyclopropanecarbonyl-amino)-pentanoic acid ((/?)-: 2-(cyclopropane-carbonyl-amino)-pentanoic acid) Substituting iV-decyloxy-D-amine 62 201120035 In addition to acid. LC/MS (ESI): [M+2]+/2: 397 » [M+l]+: 793 &gt; [M+23]+: 815. Example 74: Compound 101a Compound 101a was prepared in the same manner as in Example 68 except that (/?)-2-(cyclopropanoylamino)-hexanoic acid ((/?)-2-( Cyclopropane-carbonyl-amino)-hexanoic acid) is substituted for TV-methoxy thio-D- lysine. LC/MS (ESI): [M+2]+/2: 4M, [M+l]+: 82b[M+23]+: 843. Example 75: Compound 102a Compound 102a was prepared in the same manner as described in Example 68 except that iV-cyclopropanecarbonyl-D-valine was substituted for methoxycarbonyl- In addition to D-proline. LC/MS (ESI): [M+2]+/2: 397,[M+l]+: 793,[M+23]+: 815. Example 76: Compound 103a Compound 103a was prepared in the same manner as described in Example 68 except that iV-cyclopropanecarbonyl-D-leucine was substituted for iV-methoxy. In addition to carbonyl-D-proline. LC/MS (ESI): [M+2]+/2: 411 » [M+l]+: 821 &gt; [M+23]+: 63 843. 201120035 Example 77: Compound 104a Compound 104a was prepared in the same manner as described in Example 68 except that (/?)-2-(cyclopropanecarbonyl-amino)-3,3-dimethyl-butyric acid ( (/〇-2-(cyclopropanecarbonyl-amino)-3,3-dimethyl-butyric acid) is substituted for methoxycarbonyl-D-proline. LC/MS (ESI): [M+2]+/2 411 ♦ [M+l]+: 821 » [M+23]+: 843. Example 78: Compound 105a Compound 105a was prepared in the same manner as in Example 68 except that (/?)-cyclohexyl was used. -(-R)-cyclohexyl-(cyclopropanecarbonyl-amino-acetic acid) is substituted for iV-methoxyl-D-proline. LC/MS ( ESI): [M+2]+/2: 437, [M+l]+: 873, [M+23]+: 895. Example 79: Compound 106a Compound 106a was prepared in the same manner as in Example 68. Except for the use of N-methoxycarbonyl-L-alanine in place of indolemethoxycarbonyl-D-proline. LC/MS (ESI): [M+ 2]+/2 : 359 » [M+l]+ : 717 &gt; [M+23]+ : 739. Example 80: Compound 10&quot;7a 64 201120035 Compound 107 a was prepared in the same manner as in Example 68 except that (5)-2-methoxycarbonyl-amino-butyric acid was substituted for the methoxycarbonyl group. -D-proline acid LC/MS (ESI): [M+2]+/2: 373 &gt; [M+l]+: 745 » [M+23]+: 767 » Example 81: Compound 108a Compound 108a was prepared in the same manner as described in Example 68 except that 〇S)-2·methoxy-amino-pentanoic acid was substituted for methoxy. LC/MS (ESI): [M+2]+/2: 387 &gt; [M+l]+: 773 &gt; [M+23]+: 795. Example 82: Compound 109a Compound 109a was prepared in the same manner as in Example 68 except that (5)-(2-J-methoxycarbonyl-amino-hexanoic acid) was used instead of iV. - alkoxy-based group - D- lysine. LC/MS (ESI): [M+2]+/2: 401 &gt; [M+l]+: 801 &gt; [M+23]+: 823. Example 83: Compound 11A Compound 110a was prepared in the same manner as in Example 68 except that methoxycarbonyl was substituted with V-methoxycarbonyl-L-leucine. -D-proline acid. LC/MS (ESI): [M+2]+/2: 401 &gt; [M+l]+ : 801 &gt; [M+23]+ : 65 201120035 823. Example 84: Compound 111a Compound 111a was prepared in the same manner as in Example 68 except that (S)-2-methoxycarbonylamino-3,3-dimethyl-butyric acid (〇S)- 2-methoxycarbonylamino-3,3-dimethyl-butyric acid) is substituted for methoxycarbonyl-D-proline. LC/MS (ESI): [M+2]+/2: 401 » [M+l]+ : 801 « [M+23]+ : 823. Example 85: Compound 112a Compound 112a was prepared in the same manner as described in Example 68 except that the methoxycarbonyl-L-valine was substituted for the methoxycarbonyl-D- In addition to proline. LC/MS (ESI): [M+2]+/2: 387, [M+l]+: 773,[M+23]+: 795. Example 86: Compound 113a Compound 113a was prepared in the same manner as in Example 68 except that #-ethoxycarbonyl-L-valine was substituted for the methoxycarbonyl group. In addition to D-proline. LC/MS (ESI): [M+2]+/2: 401 &gt; [M+l]+: 801 » [M+23]+: 823. Example 87: Compound 114a 66 201120035 Compound 114a was prepared in the same manner as described in Example 68 except that the methoxycarbonyl group was replaced with phenoxy-L-valine (7V~phenoxycarbonyl-L-valine). In addition to D-proline. LC/MS (ESI): [M+2]+/2: 449 &gt; [M+l]+: 897 &gt; [M+23]+: 919. Example 88: Compound 115a Compound 115a was prepared in the same manner as in Example 1, except that /V-Boc-D-proline was used. (iV~Boc-D-Proline) was substituted for _/V~Boc-L. - other than valine. LC/MS (ESI): [M+l]+: 411. Example 89: Compound 116a Compound 116a was prepared in a similar manner to that described in Example 2. LC/MS (ESI): [M+l]+: 409. Example 90: Compound 117a Compound 117a was prepared as described in Example 3 except that Compound 1a was used instead of Compound 2a. LC/MS (ESI): [M+l]+: 456. Example 91: Compound 118a Compound 118a was prepared in the same manner as in Example 4 except that Compounds 116a and 117a were used instead of Compounds 2a and 3a. LC/MS (ESI), [M+l]+: 659. 67 201120035 Example 92: Compound 119a Compound 119a was prepared from compound 118a in a procedure similar to that described in Example 5. LC/MS (ESI): [M+2]+/2: 230 » [M+l]+: 459 &gt; [M+23]+: 481. Example 93: Compound 120a Compound 120a was prepared in the same manner as described in Example 68 except that methoxycarbonyl-D was substituted with Ar-Boc-L-phenylglycine. · In addition to valine. LC/MS (ESI): [M+2]+/2: 463: [M+l]+: 925 &gt; [M+23]+: 947. Example 94: Compound 121a Compound 121a was prepared in the same manner as in Example 68 except that instead of methoxycarbonyl-------------------------- In addition to D-proline. LC/MS (ESI): [M+2]+/2: 463,[M+l]+: 925,[M+23]+: 947. Example 95: Compound 122a Compound 122a was prepared in the same manner as described in Example 68 except that jV-Boc-l-phenylglycine was substituted for 7V-decyloxycarbonyl. -D-proline and using 119a instead of 5a" 68 201120035 LC/MS (ESI) : [M+2]+/2 : 463,[M+l]+ : 925,[M+23]+ : 947 〇 Example 96: Compounds 123a and 124a Compounds 122a and 124a were prepared in the same manner as described in Example 46 except that cyclopropanecarbonyl chloride was used in place of acetamidine and 120a was used in place of 6a. LC/MS (ESI): [M+2]+/2: 431 » [M+l]+: 861 · [M+23]+: 883. Example 97: Compounds 125a and 127a Compounds 125a and 127a were prepared in the same manner as described in Example 46 except that the cyclopropanecarbonyl chloride was used in place of ethylene oxide and 121a was used in place of 6a. LC/ MS (ESI): [M+2]+/2: 43^ [M+l]+: 861 &gt; [M+23]+: 883. Example 98: Compounds 126a and 127a Compounds 126a and 127a were prepared in the same manner as described in Example 46 except that cyclopropanecarbonyl chloride was used instead of ethane and 122a was used instead of 6a. LC/MS (ESI): [M+2]+/2: 431: [M+l]+: 861 &gt; [M+23]+: 883 » Example 99: Compound 128a 69 201120035 Compound 128a The procedure described in Example 68 was followed except that D- lysine (D-valine) was used in place of JV-decyloxy-D-lysine. LC/MS (ESI): [M+l]+: 657. Example 100: Compound 129a Compound 129a was prepared in the same manner as described in Example 68 except that L- chloroline acid (L-valine) was used in place of the methoxyl-D-manucleic acid. LC/MS (ESI): [M+l]+: 657. Example 101: Inhibition of HCV replication The inhibitory activity of the compounds of the invention against HCV, according to the method described by Lee et al. (Lee ei a., Anal. Biochem., 316: 162-70 (2003) and Lee ei a/ J. Virol Methods, 116:27-33 (2004)), assessed using a reporter-based cell line Ava5-EG (A4AB) SEAP. Briefly, Ava5_EG (MAB) SEAP cells were cultured in a medium containing 500 pg/mL G418 (geneticin) and 10 pg/mL blasticidin in a 5% C〇2 environment incubator. Culture, in which G418 and Insecticide Biotech Co., Ltd. (Invitrogen, Carlsbad, CA) » Seed cells in 96-well plates (1 μμί 5×10 3 cells per well) at 37 ° C After culturing for 24 hours, the cells were treated with different concentrations of the test compound DMSO solution. After 48 hours, the medium of each well was replaced with fresh medium containing the same concentration of the test compound, so that any cells secreted and accumulated in the medium were removed. Authenticated alkaline phosphatase (SEAP), the cells were cultured for an additional 24 hours, then the medium was collected and the luminescence assay kit was used (Phospha-Light assay kit, 201120035 Ding 1'〇卩1\,?〇8161&gt;, 〇八,118八) Test 8 8 of them? active. Compounds 6a, 7a-A, 7b-A, 7c-A, 7a-B, 7b-B, 7c-B, 25a, 26a' 29a, 30a, 33a' 34a, 37a, 38a, 41a, 42a' 45a, 46a 50a-77a, 80a, 81a, 84a, 85a, 88a-98a and 100a-129a were tested in this assay and all tested compounds inhibited HCV replication, with the surprising fact that compounds 6a, 7a-A , 7b-A, 7c-A, 7a-B, 7b-B, 7c-B, 25a, 26a, 29a, 30a, 33a, 34a, 37a, 38a, 41a, 42a, 45a, 46a, 50a, 51a, 52a , 54a, 56a, 58a, 60a ' 61a ' 66a, 67a, 68a, 70a, 74a ' 76a ' 84a, 90a and 92a exhibit EC5G values (ie, 50% HCV replication is inhibited by the test compound) Below 0.5 μΜ, and even more surprisingly, compounds 50a, 52a, 54a, 56a, 60a, 66a, 68a, 90a and 92a exhibit an EC5 enthalpy of less than 0.04 μΜ. Example 102: Cytotoxicity analysis The viability of cells after treatment (see Example 43 above) was determined by MTS analysis as described by Cory et al. (Cory et al., Cancer Commun., 3:207-12 (1991)). . Briefly, Ava5-EG (A4AB) SEAP cells were treated with the aforementioned test compound. After 48 hours, each medium was replaced with fresh medium containing the same concentration of test compound, and the cells were further cultured for 24 hours in each well. Add 100 μM solution, which contains DMEM (without phenol red), [3-(4,5-dimethyl 0-but-2-yl)-5-(3-histyloxyphenyl) -2-(4-Phenylphenyl)-2H-tetrazole R-]([3-(4,5-dimethylthiozol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl -2H-tetrazolium, inner salt], Promega, Madison, WI), and 吩 桊 桊 旨 旨 71 201120035 (phenazine methosulfate, Sigma, St. Louis, MO) and the ratio is 80:20:1. Thereafter, the cells were cultured in an incubator at 370 C in a 5% CO 2 atmosphere for 1-4 hours, and the absorbance at 490 nm of each well was measured. Compounds 6a, 7a-A, 7b-A, 7c-A, 7a-B, 7b-B, 7c-B, 25a, 26a, 29a, 30a, 33a, 34a, 37a, 38a, 41a, 42a, 45a, 46a , 50a-77a, 80a, 81a, 84a, 85a, 88a-98a and l〇〇a_129a were tested in this analysis, which surprisingly showed the CCso value exhibited by all compounds tested (ie killing 50) The concentration of the test compound in % cells is about 50 μΜ. Other Embodiments All of the features disclosed in this specification can be combined in any manner. Features disclosed in this specification can be replaced by another feature of the same, equivalent, or similar purpose. Therefore, unless otherwise indicated, the features disclosed are only examples of the generic equivalent or similar features. From the above description, the present invention can be easily understood by those skilled in the art, and various modifications and changes can be made to the present invention without departing from the scope of the invention. Therefore, other specific embodiments are also within the scope of the present patent application. [Simple description] None [Main component symbol description] 72 201120035

Claims (1)

201120035 VII. Patent application scope: i - compound of formula (I): C and D are each an arylene or heteroarylene; Rl, R_2, R4, R5 and Κ·6 are each an alkyl group, a dilute group, a block group, an aryl group, a heteroaryl group, a cycloalkyl group, a cycloalkene group. Alkyl, heterocycloalkyl, dentate, heterocycloalkenyl, cyano or nitro; R7 and Rg are each anthracene, alkyl, dilute, fast radical, aryl, heteroaryl, cycloalkyl, cycloalkenyl a heterocyclic alkyl group or a heterocycloalkenyl group; R9&amp;R1() are each an anthracene or an alkyl group; Ru and R12 are each independently an anthracene, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a cycloalkyl group. , cycloalkenyl, heterocycloalkyl or heterocycloalkenyl: X丨 and X2 are each C(O) or C(S); 74 201120035 t Yl and Y2 are absent or individually SO, s〇2, c ( o), c(o)o, C(0)NRa, C(S)NRa or S02NRa, wherein 1 is 1 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; m and η Individuals are 〇, i, 2, 3 or 4; p and q are 〇 or i; r and t are 丨, 2 or 3; and u and v are 〇, 1, 2, 3, 4, 5, respectively. 6, 7 or 8. 2. The compound of claim 1, wherein the compound is of formula (II): Formula (II). Wherein, A and B 3· are as described in claim 2, each of which is And C and D are each a phenylene group. 4. The compound according to claim 3, wherein 乂^ and X2 are each C(O) and Y丨 and Υ2 are individually s〇2, c(0) Or c(o)o. 5. The compound of claim 4, wherein each of the feet 7 and r8 is a phenyl group. 6) The compound of claim 5, wherein R&quot; and R!2 are each a Cw alkyl group or a c3.5 cycloalkyl group. 75. The compound of claim 6, wherein tAr is 2 each. A and B A and B 8. The compounds described in the scope of claim 2, wherein are different and each of C and D is a phenylene group. 9. The compound of claim 1, wherein each of and c and D are each a phenylene group. The compound of claim 9, wherein &amp; and Rg are each a stupid base. 11. The compound of claim 10, wherein Rii and 1^2 are each a Cy alkyl group or a (3:5 cycloalkyl group). , the compound is of formula (II): 13. The compound according to claim 1, wherein each of R7 and Κ·8 is a phenyl group. 14. The compound of claim 13, wherein R12 is independently CU5 alkyl or C3.5 cycloalkyl. 15. The compound of claim 14, wherein the compound is of formula (II): 76 201120035 The compound of claim 1, wherein Ri and 1^2 are each a C1-5 alkyl group or a C3.5 cycloalkyl group. 17. The compound of claim 1, wherein each is 2. 18. The compound of claim 1, wherein p, m, η, q, u, and v are 0. 19. The compound of claim 1, wherein p, m, i^q are each 〇, each is 1 and each of the ruler 5 and the ruler 6 is ρ. 20. The compound of claim 3, wherein the compound is of formula (III): Formula (III). Wherein r7 21. The compound according to claim 20 and Rg is a phenyl group. 22. The compound of claim 21, wherein Ri| and Ru are each an alkyl group, a cycloalkyl group or a heterocycloalkyl group. 23. The compound of claim 22, wherein Ru and R 2 are each a heterocycloalkyl or alkyl group substituted with an amino or heterocycloalkyl group. 77. The compound of claim 1, wherein the compound is compound 6a, 7a-A, 7b-A, 7c-A, 7a-B, 7b-B, 7c-B, 25a, 26a, 29a, 30a, 33a, 34a, 37a, 38a, 41a, 42a, 45a, 46a, 50a, 51a, -92a, 95a-114a, 123a-153a. 25. A method of treating hepatitis C virus infection comprising: providing an effective dose of a compound of claim 1 to a desired subject. 26. A pharmaceutical composition comprising: a compound of claim 1 and a pharmaceutically acceptable carrier. 78 201120035 IV. Designation of the representative representative: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (R6W where A, B, C, D, Ri, R&gt; 2, Κ·3, Κ·4, Κ·5, Κ·6, 尺 7, R8, R9, R10, Rn, R12, m, η , ρ, q, r, t, u, and ν are defined in the text. Formula (II). The compound according to claim 1, wherein Ri and Han 12 are each a CU5 alkyl group or a C3_5 cycloalkyl group. G 17. The compound of claim 1, wherein each is 2. 18. The compound of claim 3, wherein p, m, η, q, u, and v are 0. 19. If you apply for a patent scope! The compound according to the invention, wherein p, m, η and q are each 〇, u and v are each 1 and each of the ultra 5 and the ulnar 6 is ρ. 20. The compound of claim 3, wherein the compound is of formula (III): 21. The compound of claim 20, wherein Rg is phenyl. Formula (III). The compound of claim 21, wherein Rn and R12 are each an alkyl group, a cycloalkyl group or a heterocycloalkyl group. 23. The compound according to claim 22, Wherein Rn and Ri2 are each a heterocycloalkyl group or an alkyl group substituted with an amino group or a heterocycloalkyl group. The compound of claim 1, wherein the compound is compound 6a, 7a-A, 7b-A, 7c-A, 7a-B, and the compound of claim 1, wherein the compound is compound 6a, 7a-A, 7b-A, 7c-A, 7a-B. 7b-B, 7c-B, 25a, 26a, 29a, 30a, 33a, 34a, 37a, 38a, 41a, 42a, 45a, 46a, 50a, 51a, -92a, 95a-114a, 123a-153a. 25* A pharmaceutical composition comprising: a compound of claim 1 and a pharmaceutically acceptable carrier. 26. The pharmaceutical composition of claim 25, which is for use in the treatment of hepatitis C virus infection. 78